Pyrrolidine dithiocarbamate inhibits mouse acute kidney injury induced by diclofenac by targeting oxidative damage, cytokines and NF-kappa B activity

Author(s)

Borghi, Sergio M. ^[1] ; Fattori, Victor ^[1] ; Ruiz-Miyazawa, Kenji W. ^[1] ; Bertozzi, Mariana M. ^[1] ; Lourenco-Gonzalez, Yuri ^[1] ; Tatakihara, Roberto I. ^[1] ; Bussmann, Allan J. C. ^[2] ; Mazzuco, Tania L. ^[2] ; Casagrande, Rubia ^[3] ; Verri, Jr., Waldiceu A. ^[1]

Affiliation

^[1] Univ Estadual Londrina, Ctr Ciencias Biol, Dept Ciencias Patol, BR-86057970 Londrina, Parana - Brazil

^[2] Univ Estadual Londrina, Ctr Ciencias Saude, Lab Anat Patol, BR-86038350 Londrina, Parana - Brazil

^[3] Univ Estadual Londrina, Ctr Ciencias Saude, Dept Ciencias Farmaceut, BR-86038350 Londrina, Parana - Brazil

• Document type: Journal article
• Source: Life Sciences; v. 208, p. 221-231, SEP 1 2018.
• Web of Science Citations: 1

Abstract

Aims: Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used and effective anti-inflammatories despite the well-known side effects such as gastrointestinal damage, acute kidney injury (AKI), and cardiovascular dysfunctions. Diclofenac is among the most prescribed NSAIDs due to its efficient analgesic and anti-inflammatory properties. Patients using diclofenac possess 77% risk increase to develop AKI. Activation of NF-kappa B contributes to diclofenac-induced AKI, which is in line with the use of glucocorticoids as one of the management choices to treat AKI patients. Main methods: In this work, we investigate the efficacy of pyrrolidine dithiocarbamate (PDTC) in diclofenac-induced AKI in mice given it is a known NF-kappa B inhibitor. Key findings: We observed that diclofenac increased proteinuria and urine neutrophil gelatinase-associated lipocalin (NGAL), blood levels of urea, creatinine, oxidative stress, C-reactive protein (CRP), and pro-inflammatory cytokine after 24 h of a bolus administration. In renal tissue, diclofenac also induced morphological changes consistent with kidney damage, modulated cytokine production, increased oxidative stress and reduced antioxidant defenses. These alterations induced by diclofenac were accompanied by activation of NF-kappa B in the kidney. Treatment with PDTC dose-dependently reduced diclofenac-induced blood urea, creatinine, and oxidative stress. In addition, PDTC reduced proteinuria and urine NGAL levels and blood CRP and pro-inflammatory cytokines. In the kidney, PDTC inhibited diclofenac-induced morphological changes, pro-inflammatory cytokine production, oxidative stress, and NF-kappa B activation, and increased antioxidant defenses and anti-inflammatory cytokine IL-10. Significance: Our data demonstrate that PDTC ameliorates diclofenac-induced AKI and that targeting NF-kappa B signaling pathway is a promising therapeutic approach for the treatment of diclofenac-induced AKI. (AU)

• FAPESP's process: 13/08216-2 - CRID - Center for Research in Inflammatory Diseases
• Grantee: Fernando de Queiroz Cunha
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC